The application proposes to continue examining the molecular and cellular mechanisms of ischemic preconditioning (PC). During the current years' funding we demonstrated the role of multiple kinases including receptor tyrosine Idnases and stress-regulated mitogen-activated protein kinases in PC and established an essential role of nuclear transcriptional factor NFkappaB. Our studies also demonstrated that PC potentiates a survival signal by activating several anti-apoptotic genes and transcription factors simultaneously blocking the proapoptotic factors leading to the inhibition of apoptosis, which is now showed to independently contribute to myocardial infarction. While, PC has been proven to be the most powerful and state-of-the-art technique for cardioprotection, its clinical applicability is limited. Not only very limited studies exist in the literature to determine if PC could protect diseased hearts, the results are also confusing. We, therefore, propose to study if the cardioprotective abilities of PC are equally applicable to diseased hearts. We selected three most problematic diseased states: cardiomyopathy, hypertension and atherosclerosis which were found relatively less responsive to PC stimulus. We have already established our models to study these diseased hearts. Since adenosine, protein kinase C, protein tyrosine kinase, MAP kinases and KATP channels are the principle regulators for PC; we plan to determine the status of these factors in the diseased hearts. We anticipate inherent problems in one or more of these factors; and we will attempt to correct the deficiency by exogenous supplementation or by devising means to augment the deficient factors. We also anticipate reduced cardiac defense system in the diseased hearts, which consist of several intraceliular antioxidants and heat shock proteins. Again, we will attempt to precondition these hearts by devising methods to augment these defense elements. Our ultimate objective is to apply the preconditioning modality to protect diseased hearts which are resistant to preconditioning stimulus.